Design, Synthesis, and Structure–Activity Relationship Study of Novel Indole-2-carboxamide Derivatives as Anti-inflammatory Agents for the Treatment of Sepsis

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• 作者：Zhiguo Liu ; Longguang Tang ; Heping Zhu ; Tingting Xu ; Chenyu Qiu ; Suqing Zheng ; Yugui Gu ; Jianpeng Feng ; Yali Zhang ; Guang Liang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 26, 2016
• 年：2016
• 卷：59
• 期：10
• 页码：4637-4650
• 全文大小：624K
• 年卷期：0
• ISSN：1520-4804

文摘

Sepsis is characterized by a systemic inflammatory response syndrome. Derivatives of indole have been reported to exhibit diverse biological activities. This study reports on the design and synthesis of a new series of indole-2-carboxamide derivatives, which are screened for their anti-inflammatory activities in RAW 264.7 macrophages. A majority of these derivatives effectively inhibited lipopolysaccharides (LPS)-induced expression of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). Preliminary structure–activity relationship analysis was also conducted. The results indicate that the most promising compounds in the prepared series were 14f and 14g. They were found to effectively reduce LPS-induced pulmonary inflammation and overexpression of a series of inflammatory mediators. Furthermore, in vivo administration of 14f and 14g resulted in remarkable lung histopathological improvements in mice without toxicity in organs. Taken together, these data indicate that the newly discovered indole-2-carboxamide derivatives could be particularly useful for further treatment in inflammatory diseases.